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Chiral 3-hydroxypyridin-4-one derivatives, synthesis and application thereof
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A technology of hydroxypyridine and derivatives, applied in the field of chiral 3-hydroxypyridin-4-one derivatives and their synthesis and application
Active Publication Date: 2012-11-21
ZHEJIANG UNIV +2
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In addition, the oil-water partition coefficient of 3-hydroxypyridin-4-one derivatives has a great influence on its distribution and toxicity in vivo
Therefore, the compounds we design introduce alkyl groups of different sizes on the chiral site to achieve the purpose of regulating the fat solubility of the compound. For example, the chiral site of compound IV-b is connected to benzyl, while the compound IV-a The methyl group is connected, so the lipophilicity of compound IV-b is relatively stronger, and it is easier to pass through the cell membranes and key barriers of various tissues, such as the blood-brain barrier and placental barrier, thereby affecting its distribution in vivo
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Embodiment （ 1
[0065] Example 1, 3-benzyloxy-2-methyl-4 H -pyran-4-one
example 1
[0066]
[0067] Dissolve 122.3g NaOH in 278mL water, pour it into 1160mL ethanol solution of 390g malt powder, mix well, pour 422g benzyl chloride under stirring, heat and stir at 60°C for 3.5h after mixing well. After the reaction system is cooled, remove solid impurities by suction filtration, wash the filter residue with ethanol, combine it with the filtrate and spin dry, dissolve the remaining substance with dichloromethane, then wash with 5% NaOH, and finally wash with an appropriate amount of water, and wash the organic layer with After drying with anhydrous sodium sulfate, spin the solvent to obtain a light yellow oily liquid. After cooling, recrystallize with ether to obtain crystals with a yield of 78% and a melting point of 56-57°C.
[0068] Example 2, 3-benzyloxy-2-ethyl-4 H -pyran-4-one
example 2
[0069]
[0070] Dissolve 122.3g NaOH in 278mL water, then pour it into 1160mL ethanol solution of 390g malt powder, after mixing evenly, pour 422g benzyl chloride under stirring, heat and stir at 60°C for 3.5h after mixing well, the reaction system is cooled Finally, remove solid impurities by suction filtration, wash the filter residue with ethanol, combine it with the filtrate and spin dry, dissolve the remaining substance with dichloromethane, then wash with 5% NaOH, and finally wash with an appropriate amount of water, and the organic layer is washed with anhydrous sulfuric acid After the sodium is dried, the solvent is spin-dried to obtain a light yellow oily liquid. After cooling and recrystallization with ether, crystals can be obtained. The yield is 83%, and the melting point is 84-85°C. 1 HNMR (CDCl 3 ): δ=1.0 (t, 3H), 2.55 (q, 2H), 5.13 (s, 2H), 6.3 (d, 1H), 7.35 (s, 5H), 7.6 (d, 1H).
[0071] Example 3, ( S )-3-Hydroxy-1-(1-hydroxypropane-2-)-2-methylpyridine-4...
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Abstract
The invention provides a series of chiral 3-hydroxypyridin-4-one derivatives and their salts. Specifically, methyl / ethyl maltol (compound V) is reacted with benzyl chlorine (compound VI) to produce 3-benzyl-protected maltol (compound VII), then compound VII is reacted with different chiral aminoalcohols (compound VIII) to produce chiral 3-benzyloxypyridine-4-one (compound IX), and finally compound IX (chiral 3-benzyloxypyridine-4-one) is subjected to hydrogenation reduction under the catalysis of palladium carbon for deprotection, so that chiral 3-hydroxypyridin-4-one derivatives (compound I)can be obtained. In the invention, 3-hydroxypyridin-4-one derivatives are subjected to an optimal design and chiral substituents are added, so that the biological activity of chelated iron ions is improved while the toxicity is reduced. Meanwhile, the 3-hydroxypyridin-4-one derivatives of the invention are orally active and enjoy remarkable de-ironing capability. Experiments confirm that the treatment effect of the 3-hydroxypyridin-4-one derivatives on iron overload is significantly better than the effect of compound CP20, so that the derivatives provided in the invention can be applied to the preparation of medicaments for resisting symptoms of iron ion overload. The mother nucleus of the derivatives of the invention is represented by the formula I.
Description
technical field [0001] The invention belongs to the patent of drug synthesis and biological effect, and aims to develop a new chiral 3-hydroxypyridin-4-one iron ion (III) chelating agent with medicinal value. Toxic symptoms, such as thalassemia and other diseases dependent on long-term massive blood transfusions, and damage caused by excessive accumulation of iron ions in local tissues are of particular medicinal value. Background technique [0002] Many human and veterinary diseases are associated with excessive accumulation of metal elements such as iron in the body. In these diseases, excess iron accumulates in various tissues. This is called iron overload disease, formerly known as For siderosis hemorrhage. Excessive iron elements mainly come from the following sources, 1) long-term massive blood transfusion, 2) diseases such as anemia stimulate the gastrointestinal tract to absorb excessive iron elements. Repeated massive transfusions are necessary in some severe anem...
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